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Pharmacological inhibition of PRKDC-mediated DNA damage response by 3-hydroxyflavone selectively alleviates MLL-rearranged acute myeloid leukemia

ABSTRACT: Genetic rearrangements involving mixed lineage leukemia (MLL-r) in acute myeloid leukemia (AML) have been associated with resistance to chemotherapy, and there is currently a clinical unmet need for effective targeted therapies. In this study, we performed high-throughput drug screening and identified 3-Hydroxyflavone (3-HF) as a selective inhibitor of the survival and growth of MLL-r AML cells, while having minimal effects on leukemia cells with wildtype MLL. Mechanistically, 3-HF suppresses the transcription of MLL-targeted genes and exerts antileukemic activity by disrupting PRKDC-mediated DNA damage repair. Additionally, 3-HF enhances chemosensitivity in MLL-r AML cells and demonstrates synergistic antileukemic effects when combined with cytarabine, a standard chemotherapy agent, both in vitro and in vivo using two distinct mouse models of murine MLL-AF9 and human MLL-AF4 leukemia. Our findings provide a novel strategy and targeted therapeutic drug disrupting PRKDC-mediated DNA damage repair pathways for MLL-r leukemia.

ORGANISM(S): Homo sapiens

PROVIDER: GSE338690 | GEO | 2026/07/21

REPOSITORIES: GEO

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Agonistic targeting of TLR1/TLR2 induces p38 MAPK-dependent apoptosis and NfkB-dependent differentiation of AML cells

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2015-08-04 | E-GEOD-71687 | biostudies-arrayexpress

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Project description:Using a mouse model of human MLL-AF9 leukemia, we identified the lysine-specific demethylase KDM1A (LSD1 or AOF2) as an essential regulator of leukemia stem cell (LSC) potential. KDM1A acts at genomic loci bound by MLL-AF9 to sustain expression of the associated oncogenic program, thus preventing differentiation and apoptosis. In vitro and in vivo pharmacologic targeting of KDM1A using tranylcypromine analogues active in the nanomolar range phenocopied Kdm1a knockdown in both murine and primary human AML cells exhibiting MLL translocations. By contrast, the clonogenic and repopulating potential of normal hematopoietic stem and progenitor cells was spared. Our data establish KDM1A as a key effector of the differentiation block in MLL leukemia which may be selectively targeted to therapeutic effect. To investigate the effects of Kdm1a KD on histone modifications, we performed chromatin immunoprecipitation followed by next-generation sequencing (ChIP-Seq) in control and Kdm1a KD MLL-AF9 AML cells for dimethyl-H3K4 and dimethyl-H3K9, as well as for trimethyl-H3K4 and trimethyl-H3K9. Dimethyl-H3K4 and dimethyl-H3K9 are targeted for demethylation by KDM1A. For each of these histone modifications, we compared the mean ChIP-Seq signal across and around protein coding genes bound by the MLL-AF9 oncoprotein (Bernt et al., 2011) with the mean signal from genes not bound by MLL-AF9 expressed at high, middle or low levels.

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Project description:Leukemia initiating cells (LICs) of acute myeloid leukemia (AML) may arise from self-renewing hematopoietic stem cells (HSCs) and from committed progenitors. However, it remains unclear how leukemia-associated oncogenes instruct LIC formation from cells of different origins and if differentiation along the normal hematopoietic hierarchy is involved. Here, using murine models with the driver mutations MLL-AF9 or MOZ-TIF2, we found that regardless of the transformed cell types, myelomonocytic differentiation to the granulocyte macrophage progenitor (GMP) stage is critical for LIC generation. Blocking myeloid differentiation through disrupting the lineage-restricted transcription factor C/EBPa eliminates GMPs, blocks normal granulopoiesis, and prevents AML development. In contrast, restoring myeloid differentiation through inflammatory cytokines “rescues” AML transformation. Our findings identify myeloid differentiation as a critical step in LIC formation and AML development, thus guiding new therapeutic approaches. Examination of chromatin accessibility in Cebpa knock-out and control conditions.

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